Evaluating the Response to Three Antiretroviral Medication Regimens in HIV-Infected Pregnant Women, Who Begin Antiretroviral Therapy Between 28 and 36 Weeks of Pregnancy, for the Prevention of Mother-to-Child Transmission

• Rapid viral load decrease (sustained until delivery) [ Time Frame: Measured through participants' study visit at delivery (approximately 36 to 40 weeks) ] [ Designated as safety issue: No ]
  Composite binary outcome measure of (1) a successful viral load (plasma HIV-1 RNA) decrease from entry to study Week 2 (Day 11-17) and viral load less than 1,000 copies/mL at all timepoints after 4 weeks on study drugs, until delivery; and (2) tolerability (remaining on the assigned study regimen).
  
  
• Tolerability of study drugs [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ] [ Designated as safety issue: No ]
  Discontinuation of one or more of the assigned study drugs prior to delivery for any reason (including loss to follow-up) will be considered a treatment failure in the efficacy analyses, except that switching only zidovudine to investigator-selected locally available nucleoside reverse transcriptase inhibitors (NRTIs) with continuation of the other two study drugs will not be considered a treatment failure. All women who received at least one dose of study drug will be evaluable for the tolerability component of the composite outcome measure.
  
  
• Maternal adverse events of greater than or equal to Grade 3 as defined in the Division of AIDS (DAIDS) toxicity table and events of any grade that lead to discontinuation of one or more of the assigned study drugs [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ] [ Designated as safety issue: Yes ]
  
• Infant adverse events of greater than or equal to Grade 3 as defined in the DAIDS toxicity table [ Time Frame: Measured through infants' last study visit at Year 4 ] [ Designated as safety issue: Yes ]
  

• Virologic suppression to less than 200 copies/mL [ Time Frame: Measured at delivery (approximately 36 to 40 weeks) ] [ Designated as safety issue: No ]
  
• Virologic suppression to below the lower limit of quantification of the assay [ Time Frame: Measured at delivery (approximately 36 to 40 weeks) ] [ Designated as safety issue: No ]
  
• Infectivity of plasma [ Time Frame: Measured during the initial 2 weeks of ARV therapy ] [ Designated as safety issue: No ]
  The ratio of virion infectivity to HIV-1 RNA level will be compared between study arms. Collection of samples for virion infectivity assays and the Day 3 visit will only be done until 15 women in each of the three arms (45 women total) with plasma HIV RNA greater than 20,000 copies/mL at entry have been enrolled into this sub-study and have provided all required samples.
  
  
• Log10 change in viral load from entry to each time point prior to delivery [ Time Frame: Measured through participants' study visit at delivery (approximately 36 to 40 weeks) ] [ Designated as safety issue: No ]
  
• Viral load in maternal blood and vaginal secretions [ Time Frame: Measured at entry, Week 2, and near delivery ] [ Designated as safety issue: No ]
  
• HIV-1 drug resistance mutations at screening, at 2-4 weeks postpartum in women who have stopped antiretroviral therapy, and at the time of inadequate virologic response (defined in the protocol) using standard and ultrasensitive genotyping methods [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ] [ Designated as safety issue: No ]
  
• Maternal Tregs, Tacts, inflammatory and regulatory cytokines and biomarkers [ Time Frame: Measured at enrollment and prior to delivery (36 to 38 weeks gestation) ] [ Designated as safety issue: No ]
  
• Infant inflammatory and regulatory cytokines and biomarkers, and innate (NK) and adaptive immune responses (cell-mediated and antibody responses to vaccines) [ Time Frame: Measured at Weeks 2-4, 16, and 52 ] [ Designated as safety issue: No ]
  
• Number of participants who experience a stillbirth [ Time Frame: Measured through participants' last study visit at delivery (approximately 36 to 40 weeks) ] [ Designated as safety issue: No ]
  
• Number of participants who experience a premature birth (less than 32 or less than 37 weeks gestation) [ Time Frame: Measured through participants' last study visit at delivery (approximately 36 to 40 weeks) ] [ Designated as safety issue: No ]
  
• Number of infants with a low birth weight (less than 1500 or less than 2500 grams) [ Time Frame: Measured through participants' last study visit at delivery (approximately 36 to 40 weeks) ] [ Designated as safety issue: No ]
  
• Infant HIV infection status (per International Maternal Pediatric Adolescent AIDS Clinical Trials Group [IMPAACT] definitions) [ Time Frame: Measured through infants' last study visit at Year 4 ] [ Designated as safety issue: No ]
  
• Measurements of infant IQ scores (from the Bayley and Wechsler scales) [ Time Frame: Measured through infants' last study visit at Year 4 ] [ Designated as safety issue: No ]
  
• Measurements of infant executive functioning skills (from the BRIEF questionnaire) [ Time Frame: Measured through infants' last study visit at Year 4 ] [ Designated as safety issue: No ]
  
• Measurements of infant neurodevelopmental deficits (from the Ten Questions Questionnaire and the Ages and Stages Questionnaire) [ Time Frame: Measured through infants' last study visit at Year 4 ] [ Designated as safety issue: No ]
  
• Incidence of drug resistance in HIV-infected infants [ Time Frame: Measured through infants' last study visit at Year 4 ] [ Designated as safety issue: No ]
  
• Measurement of population CL/F [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ] [ Designated as safety issue: No ]
  
• Measurement of population V/F [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ] [ Designated as safety issue: No ]
  
• Measurement of population t 1/2 [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ] [ Designated as safety issue: No ]
  
• Individual predicted empiric Bayesian CL/F [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ] [ Designated as safety issue: No ]
  
• Individual predicted empiric Bayesian V/F [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ] [ Designated as safety issue: No ]
  
• Individual predicted empiric Bayesian t 1/2 [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ] [ Designated as safety issue: No ]
  
• Individual predicted empiric Bayesian steady-state pre-dose concentrations [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ] [ Designated as safety issue: No ]
  
• Individual predicted empiric Bayesian area under the curve (AUC) [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ] [ Designated as safety issue: No ]
  
• Cord-to-maternal plasma concentration ratio [ Time Frame: Measured through participants' study visit at delivery (approximately 36 to 40 weeks) ] [ Designated as safety issue: No ]
  
• ARV concentrations in vaginal secretions [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ] [ Designated as safety issue: No ]
  
• ARV concentrations in plasma [ Time Frame: Measured through participants' last study visit 24 weeks after giving birth ] [ Designated as safety issue: No ]
  

While there are many ARV medications and combination regimens available to treat HIV-infected people, the number of ARV medications studied in HIV-infected pregnant women for the prevention of mother-to-child transmission remains limited. HIV-infected pregnant women who begin taking ARV medications late in their pregnancies require effective therapy to reduce the risk of transmitting HIV to their children. Currently, there is no data available that compares the effects of non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PIs), and integrase inhibitors (which are three classes of ARV medications) in women who begin taking ARV medications late in their pregnancies. The purpose of this study is to compare the safety, tolerance, and virologic and immunologic responses to three different medication regimens, each including an NNRTI, PI, or integrase inhibitor, in pregnant HIV-infected women who begin ARV therapy late in their pregnancies (i.e., a gestational age between 28 and 36 weeks).

Participants in this study will be randomly assigned to one of three arms. Participants in Arm A will receive lamivudine 150 mg/zidovudine 300 mg twice a day and lopinavir 600 mg/ritonavir 150 mg twice a day. Participants in Arm B will receive lamivudine 150 mg/zidovudine 300 mg twice a day and efavirenz 600 mg each night. Participants in Arm C will receive lamivudine 150 mg/zidovudine 300 mg twice a day and raltegravir 400 mg twice a day. All participants will receive their assigned medications from study entry through delivery. Participants will attend study visits at entry; Day 3; and Weeks 1, 2, 4, 6, and 36 to 38. Study visits will include a medical history review, physical examination, questionnaires, and blood collection. Some study visits will include a vaginal swab procedure.

While participants are in labor, they will receive intravenous zidovudine and oral lamivudine, along with the other medications they have been receiving. Participants will have a physical examination and blood collection, and study researchers will collect blood from the placenta and collect a sample of amniotic fluid from women having a cesarean delivery. After delivery, some women will continue to receive ARV medications according to the local guidelines. Participants will attend study visits following the delivery at Weeks 2 to 4, 6, 16, and 24, which will include a medical history review, physical examination, and blood collection. One study visit will include a vaginal swab procedure. Some participants may have vaginal specimens stored for future research.

Participants' babies will receive ARV medications as prescribed by the babies' doctors. Study visits for babies will occur at birth; Weeks 2 to 4, 6, 16, and 24; and Years 1, 2, 3, and 4. Each study visit will include a medical history review and physical examination. Select visits will include a blood collection and neurodevelopmental and neuropsychological evaluations.